PROJECT SUMMARY The formation of an abdominal aortic aneurysm is a complex biological and mechanical process that has as a central feature the biological processes that result in a dysregulation of reactive oxygen species (ROS) in the arterial wall. This is reflected in structural changes in the arterial wall that begin as relatively subtle changes in extracellular matrix structure and function and ultimately proceed to cell loss. These structural changes in the arterial wall are manifest as abnormalities in the mechanical properties of the vessel that eventually result in the formation of aneurysms. Through the use of transgenic mouse models that overexpress catalase, we have identified H2O2 as a pivotal mediator of abdominal aneurysm formation. The central goal of this proposal is to better define the functional importance of the critical signaling pathways that govern H2O2 via regulation of catalase expression as a platform for developing mechanism-targeted therapeutics for the treatment of abdominal aortic aneurysms and for a better understanding of the variability in the disease process that occurs in humans. In this proposal, we have three major goals. First, we would like to better understand the regulation of catalase expression in the arterial wall at a much more mechanistic level as it pertains to changes in arterial stiffness and abdominal aortic aneurysm formation. Second, we would like to take the knowledge gained from our mechanistic studies and perform initial therapeutic studies using a novel biomechanical delivery system that we have co-developed to prevent and treat abdominal aortic aneurysms. Finally, we will extend these studies to humans and study the impact of differences in catalase expression that occur as the result of a known functional polymorphism in the promoter region of the human catalase gene on arterial biomechanics in a well characterized human cohort of subjects at risk for cardiovascular disease. Through these studies, we hope to not only better understand how abdominal aortic aneurysms form, but also to gain insights into therapeutic strategies and to perhaps develop a better understanding of disease variability in humans.